There is still a need in the art for cytotoxic agents for use in cancer therapy. In particular, there is a need for cytotoxic agents which inhibit or treat the growth of tumors which have an effect similar to paclitaxel and interfere with the process of microtubule formation. Additionally, there is a need in the art for agents which accelerate tubulin polymerization and stabilize the assembled microtubules.
Described in copending case, application No. 60/505,544, filed Sep. 24, 2003 is a series of 6-[(substituted)phenyl]-triazolopyrimidine compounds having the structural formula
which are microtubule inhibitors and useful in the treatment of cancer.
Useful in the preparation of the above described 6-[(substituted)phenyl]-triazolopyrimidine compounds are a series of substituted amino alcohols of the formula HO—(CH2)n—NR1R2.
Described by Kabalka, George W.; Li, Nan-Sheng; and Pace, R. David, Synthetic Communications (1995), 25(14), 2135-43 is the preparation of amino alcohols by the N-t-butoxycarbonyl protection of primary and secondary amines via a hydroboration-oxidn reaction sequence.
Disclosed by Artyushin, O. I.; Petrovskii, P. V.; Mastryukova, T. A.; Kabachnik, M. I. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1991), (9), 2154-7 is the simple synthesis of 3-(alkylamino)-1-propanols by condensing for example NH2(CH2)3OH with ClCO2Me in CH2Cl2 containing Na2CO3 which gave MeNH(CH2)3OH in 37% yield.
A. Parkkinen et al, Journal of Physical Organic Chemistry, (1991), 4(1), 53-7 describes the hydrolytic decomposition of methyltetrahydrooxazines to afford for example MeNH(CH2)3OH.
Described by Powell, John; James, Nadine; Smith, Stuart J., Synthesis (1986), (4), 338-40 is the preparation of MeNH(CH2)3OH by the lithium aluminum hydride reduction of formamide HC(O)NH(CH2)3OH in the presence of triethanolamine.
Kashima, Choji; Harada, Kazuo; Omote, Yoshimori, Canadian Journal of Chemistry (1985), 63(2), 288-90 describe the synthetic procedures where in the presence of NaH, the methylation of H2NCH2CH2OH by Me2SO4 in THF gave mainly H2NCH2CH2OMe, MeNHCH2CH2OMe, and Me2NCH2CH2OMe, whereas with LiH or CaH2 the products were MeNHCH2CH2OH and Me2NCH2CH2OH. Similar results were obtained with H2N(CH2)3OH to give MeHN(CH2)3OH.
Described by Felfoldi, K.; Laszlavik, M.; Bartok, M.; Karpati, E. Acta Physica et Chemica (1980), 26(3-4), 163-9 is the preparation of numerous compounds which include for example MeHN(CH2)3OH by reaction of Cl(CH2)3OH with methylamine in ethanol in an autoclave in 55% yield. However, the preparation method produces a flammable solvent and so is not sufficient to prepare the substituted amino alcohols and in particular, 3-methylamino-propan-1-ol.
Katritzky, Alan R.; Baker, Victor J.; Brito-Palma, Fernando M. S. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1980), (11), 1739-45 describe the preparation for example of MeHN(CH2)3OH by reduction of C2H5OC(O)(CH2)2NHMe with lithium aluminum hydride in 56% yield.
Described by Jourdain, F.; Pommelet, J. C.; Tetrahedron Lett.; 35; 10; 1994; 1545-1548, is the preparation of amino alcohols in which the chloroalcohols are reacted with an excess of amine in the presence of ethanol or aniline in toluene.
S. D. Goldberg; and W. F. Whitmore; J. Amer. Chem. Soc.; 59; 1937; 2280-2282 describe the preparation of monoalkylaminopropanols wherein the aminopropanol is reacted with trimethylene oxide made from trimethylene bromohydrin and 50% sodium hydroxide. However, the reaction was effected by the action of trimethyleneoxide and trimethylene bromohydrin on the aminopropanol.
Described by S. Searles and V. P. Gregory; J. Amer. Chem. Soc.; 76; 1954; 2789-2790 is the preparation, for example, wherein 3-methylamino-1-propanol is formed by reaction of a 25% aqueous solution of methylamine and trimethylene oxide in an autoclave at 150° C. for 12 hours and then collecting the product by distillation.
Kurihara et al.; YKKZAJ; Yakugaku Zasshi; 74; 1954; 763; Chem. Abstr.; 1955; 11646 describe the preparation of alkylaminopropanols wherein a mixture of sodium, ammonium acetate, allyl alcohol and alkylamine are reacted in an autoclave at 130-150° C. for 7 hours. Prepared using the described conditions is for example 3-methylamino-1-propanol.
Described by Cherbuliez, E. et al.; HCACAV; Helv. Chim. Acta; FR; 50; 1967; 331-346 is the alkylation for example of amino-3-propanol-1 with methyl iodide and the product 3-methylamino-propan-1-ol is purified by chromatography.
While the above described processes may be used to prepare substituted amino alcohols there is a need for a simpler process which can be used for larger scale preparations.